Abstract 1136 Engineering yeast Hsp104 through nucleotide-binding domain 2 to counter human proteotoxicity

The yeast Hsp104 disaggregase is a powerful ATP-dependent machine that dissolves various misfolded protein states in yeast upon stress and returns them to their native, functional conformations. Leveraging Hsp104 against toxic protein aggregation in neurodegenerative diseases may provide much-needed therapeutic benefit. However, such a path is challenging since toxic disease substrates in humans have no yeast homologs and humans have no Hsp104 homolog. We have previously engineered Hsp104 to dissolve human disease substrates to overcome this challenge and enhance Hsp104 disaggregation activity while limiting off-target toxicity.